N-Acylazole mediated stereoselective and regioselective synthesis of N-substituted azole acrylonitriles

Article abstract of DOI:10.3906/kim-1903-56

Regio- and stereoselective synthesis of N -substituted azole acrylonitriles has been achieved smoothly in N, N -dimethylformamide (DMF) in the presence of potassium carbonate (K 2 CO 3) as a base catalyst. N -Substituted azole acrylonitriles were obtained

Full text of DOI:10.3906/kim-1903-56

Turk J Chem
Turkish Journal of Chemistry
(2019) 43: 1134 – 1148
© TÜBİTAK
http://journals.tubitak.gov.tr/chem/
doi:10.3906/kim-1903-56
Research Article
N -Acylazole mediated stereoselective and regioselective synthesis of
N -substituted azole acrylonitriles
Osman AYDIN,, Şule KÖKTEN,, Hakan ÜNVER,, İlhami ÇELİK∗,
Department of Chemistry, Faculty of Science, Eskişehir Technical University, Eskişehir, Turkey
Received: 21.03.2019
•
Accepted/Published Online: 16.06.2019
•
Final Version: 06.08.2019
Abstract: Regio- and stereoselective synthesis of N -substituted azole acrylonitriles has been achieved smoothly in
N, N -dimethylformamide (DMF) in the presence of potassium carbonate (K2 CO3) as a base catalyst. N -Substituted
azole acrylonitriles were obtained in moderate to good yields (39%–87%) with a one-pot reaction between readily available
1
N -acetylazoles and Baylis-Hillman nitriles. The structural determinations were accomplished by NOESY H NMR and
X-ray crystallography.
Key words: Baylis–Hillman nitriles, benzimidazole, benzotriazole, N -substituted azole acrylonitriles
1. Introduction
Benzotriazole and benzimidazole are very useful subunits for the development of the potential chemotherapeutic
agents. They act as precursors in many synthesis reactions and have proven to be versatile and valuable sources
of medicinal agents as their derivatives show various pharmaceutical activities such as antimicrobial, antifungal,
antitumor, and anthelmintic [1–5]. The literature studies based on the incorporation of benzotriazole and
benzimidazole units in order to obtain their derivatives resulted in many drugs which have been on the market
or are in clinical trials to cure many illnesses [6–8]. Among them are Vorozole [9], Alizapride [10], Albendazole
[11], and Benomyl [12] (Figure 1).
Figure 1. Some clinically important benzotriazole- and benzimidazole-based drugs.
There have been several reported works that showed some substituted acrylonitriles addressed to the
bactericidal and cytotoxic activities in human cancer cell lines. Their benzotriazolyl and benzimidazolyl
derivatives were also found to be active against both hematological and solid human tumors. Detailed structure-
activity relationship studies have been carried out and from the analysis of data, it was deduced that the presence
∗Correspondence: ilcelik@eskisehir.edu.tr
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AYDIN et al./Turk J Chem
of acrylonitrile unit is required for good activity but the presence of azole unit is also necessary for killing cells
[13,14]. On the other hand, the position of the azole ring attached to the acrylonitrile is not essential for the
activity. Another study also revealed that the loss of activity was seen after the conversion of the cyano group
into a carboxamido or carboxylic acid group [15].
Baylis–Hillman adducts offer an excellent platform for several chemical transformations because of the
presence of three functional groups including a hydroxyl group, a double bond, and an electron withdrawing
group in close proximity. They were illustrated as valuable precursors for the synthesis of heterocycles and many
biologically active molecules [16,17]. We recently reported the synthesis of several N -substituted azole acrylates
from the reaction between Baylis–Hillman adducts and N -acylazoles with quantitative yields in one-pot reaction
[18]. N -Acylazoles are very important synthetic auxiliaries in organic synthesis as they are stable crystalline
compounds and offer mild reaction conditions to prepare amides [19,20], esters, thioesters [21], ketones [22,23],
and heterocycles [24–26].
Based on their pharmacological importance and in line with our studies concerning the synthesis of azole
derivatives from Baylis–Hillman adducts, we aimed to synthesize N -substituted benzotriazolyl and benzimida-
zolyl acrylonitriles with a versatile method.
2. Results and discussion
We first prepared the starting compounds in laboratory conditions by modifying the literature methods. N -
Acetylbenzotriazoles and N -acetylbenzimidazoles were prepared by treating acetic acid with benzotriazole or
benzimidazole in the presence of N, N′ -dicyclohexylcarbodiimide at room temperature (Scheme 1). Baylis–
Hillman nitriles were prepared from the reaction between suitable aldehydes and acrylonitrile catalyzed by 1,4-
Diazabicyclo[2.2.2]octane (Scheme 2) [27,28]. Then, we started to synthesize the target compounds according
to the method we previously described to prepare N -substituted azole acrylates. N -substituted benzotriazolyl
acrylonitriles were afforded by the reaction of Baylis-Hillman nitriles with N -acetylbenzotriazole in DMF in
the presence of K2 CO3 at room temperature (Scheme 3).
Scheme 1. Synthesis of N -acetylazoles.
Scheme 2. Synthesis of Baylis–Hillman nitriles.
All the synthesized products were purified by column chromatography and their structures were identified
by NMR and FTIR spectral data. The obtained results were supported by high resolution mass spectra (HRMS).
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AYDIN et al./Turk J Chem
Scheme 3. Synthesis of N -substituted benzotriazolyl acrylonitriles.
N -Substituted benzotriazolyl acrylonitriles were synthesized in 39%–87% yields (Table 1). While it was seen that
the yields increased in the presence of electron donating groups on benzene ring in N -substituted benzotriazolyl
acrylonitriles, they decreased in the presence of electron withdrawing groups on benzene ring. In some cases,
we observed that there was another product, other than the target compound. We thought that these two
1
2
13
products are N-1 (Bt ) and N-2 (Bt ) isomers of benzotriazole according to their
C-NMR spectra. In
13
1
C-NMR spectra, while six C signals for benzotriazolyl ring in Bt isomers were observed, three C signals
for benzotriazolyl ring in Bt isomers were observed because of the symmetry in Bt rings. Comparing the
formation of Bt isomer to that of Bt isomer, in some cases, the yields of Bt compounds are much higher than
the yields of Bt compounds. For the rest, Bt was obtained as the sole product (Table 1). These results show
2
2
1
2
1
2
1
1
that the developed reactions are regioselective. On the other hand, the H-NMR spectra of 9 and 9’ consist of
singlet signals in the ranges of 6.97–7.49 ppm and 5.54–5.66 ppm, which are attributable to the vinylic-H and
the protons of –CH2 , respectively. The IR spectra of compounds also contain a strong absorption at around
2204–2263 cm−1 , confirming the presence of CN group.
Table 1. Yields of N -substituted benzotriazolyl acrylonitriles.
1
2
Entry
R
Bt Yield (%) Bt Yield (%) Overall Yield (%)
1
2
3
4
5
6
7
8
9
Ph
9a, 76
9b, 71
9c, 67
9d, 67
9e, 63
9f, 52
9g, 63
9h, 57
9’a, 11
9’b, −
9’c, 17
9’d, −
9’e, −
9’f, −
9’g, −
9’h, −
9’i, 11
87
71
84
67
63
52
63
57
39
4-Me-Ph
4-MeO-Ph
4-F-Ph
3-Cl-Ph
2,4-Cl2-Ph
4-Br-Ph
2-Furanyl
2-Thiophenyl 9i, 28
We repeated the same reaction conditions for the synthesis of N -substituted benzimidazolyl acrylonitriles
employing the Baylis–Hillman nitriles with N -acetylbenzimidazole. Reactions took place in DMF in the
presence of K2 CO3 at room temperature (Scheme 4).
All the synthesized products were purified by column chromatography and the overall yields (39%–73%)
seemed to be satisfactory (Table 2). While the yields of the obtained products increased in the presence of
electron donating groups on benzene ring in N -substituted benzimidazolyl acrylonitriles, they decreased in the
presence of electron withdrawing groups on benzene ring. The structures of isolated products were confirmed on
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AYDIN et al./Turk J Chem
Scheme 4. Synthesis of N -substituted benzimidazolyl acrylonitriles.
1
13
the basis of H- and C-NMR spectra. The obtained results were also supported by FTIR spectroscopy and
1
HRMS. In H-NMR spectra, a singlet signal assigned to the proton of CH in benzimidazole ring was observed
at around 8.02–8.05 ppm for all compounds. Moreover, vinylic proton signals resonated as singlet between 6.75
and 7.01 ppm. A singlet signal for CH2 protons was observed at around 5.06–5.58 ppm. The CN stretches in
the IR spectra of 10 are similar to those observed for 9 and 9’.
Table 2. Yields of N -substituted benzimidazolyl acrylonitriles.
Entry
R
Ph
Yield (%) Entry
R
Yield (%)
10f, 39
10g, 44
10h, 40
1
2
3
4
5
10a, 73
10b, 56
6
7
8
9
2,4-Cl2-Ph
4-Br-Ph
2-Furanyl
4-Me-Ph
4-MeO-Ph 10c, 48
4-F-Ph
3-Cl-Ph
10d, 48
10e, 48
2-Thiophenyl 10i, 48
After all the compounds were synthesized and characterized, it was thought that only one isomer was
formed among the possible geometric isomers E/Z that are said to have occurred for similar compounds in
the literature [29–32]. According to the spectral data reported in the literature, while chemical shift values of
the vinylic protons in the E -isomers appear obviously downfield of the aromatic protons, the corresponding
values for the vinylic protons of the Z -isomers are generally observed upfield or overlapped with aromatic ring
protons. In our spectral work, we observed vinylic proton signals at around 7.11–7.36 ppm for compounds 9,
7.30–7.49 ppm for compounds 9′ , and 6.75–7.09 ppm for compounds 10. Because of the upfield shift of vinylic
proton signals, we ran 2D NOESY experiments and also used X-ray method for products 9a, 9′ a, and 10a to
decide which double bond configuration is favorable.
In the 2D NOESY experiment carried out for compound 9a (Figure 2), cross sectional peaks between the
H7,8 protons resonated at 5.59 ppm and H9 and H6 protons resonated at 7.67 and 7.23 ppm, respectively, were
observed. The presence of these cross sectional peaks proved that these protons interacted spatially. Based on
the results obtained from the 2D NOESY experiment, it was thought that 9a compound has Z -configuration.
We ran the same experiment for compound 9′ a (Figure 3). Because the presence of cross sectional peaks
between H5,6 protons resonated at 5.54 ppm and H7 proton resonated at 7.35 ppm showing that these protons
interacted spatially, we concluded that 9′ a also has Z -configuration. According to the 2D NOESY experiment
run for compound 10a, cross sectional peaks between H7,8 protons resonated at 5.08 ppm and H6 , H9 , and
H13 protons resonated at 7.01, 7.43, and 7.88 ppm, respectively, were observed (Figure 4). This showed that
H7,8 protons interacted with H6 , H9 , and H13 protons spatially. Therefore, compound 10a was also thought
as Z isomer.
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AYDIN et al./Turk J Chem
Figure 2. The 2D NOESY spectrum (a) and 3D structure (b) of 9a.
Figure 3. The 2D NOESY spectrum (a) and 3D structure (b) of 9′ a.
To support the results obtained from the NOESY experiments, X-ray diffraction analysis was performed
for the same compounds (9a, 9a′ , and 10a). X-ray suitable crystals were obtained via layer diffusion using
ethyl acetate/n-hexane as solvents. The compounds thermal ellipsoid plots are given in Figure 5 with 40%
probability level and crystallographic data, refinement parameters, and selected bond lengths are shown in
Tables 3 and 4. All the hydrogen atoms were added at the detected positions. The measured bond distances
are in agreement with standard values. The measured N-N bond distances for all three compounds are close
to each other between 1.297–1.345 Å. In addition, double bond distances between nitrogen atoms were found
to be shorter than single bonds for compounds 9a (N(1)–N(2)) and 9′ a (N(2)–N(3)) as 1.297 Å and 1.313,
2
2
respectively. Due to the sp hybridization, bond distances between sp hybridized carbons were shorter than
3
those involving sp carbons in the range of 1.323–1.329 Å. From the single-crystal figures of compounds 9a,
9a′ , and 10a, it was seen that the vinylic protons and CH2 protons are close spatially (Figure 5).
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AYDIN et al./Turk J Chem
Figure 4. The 2D NOESY spectrum (a) and 3D structure (b) of 10a.
Figure 5. Thermal ellipsoid plots of the compounds 9a, 9′ a, and 10a at the 40% probability level.
Data obtained from the spectral work showed that all compounds have Z-configuration. Only one of the
possible geometric isomers was obtained with the method used here, we concluded that the developed reactions
are also found to be stereoselective. When the preparation of N -substituted azole acrylonitriles is compared
with the preparation of N -substituted azole acrylates [18], different stereoisomers have been obtained. While
Z -isomers of N -substituted azole acrylonitriles in this work are obtained, E -isomers of N -substituted azole
1
acrylates in our previously published work have been obtained. In addition to these results, N-1 (Bt ) isomer
2
of benzotriazoleboth in this work and in our previous work has been obtained more than N-2 (Bt ) isomer of
benzotriazole.
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AYDIN et al./Turk J Chem
Table 3. Crystal data and structure refinement for 9a, 9′ a, and 10a compounds.
9a
9′a
10a
CCDC Number
Formula
1850321
C16H12N4
260.30
296
0.71073
Monoclinic
P21/n
13.0856 (10), 90
7.1032 (6), 110.390(5)
15.6618 (12), 90
1364.54 (19)
4
1.267
0.079
544
1850263
C16H12N4
260.30
296 (2)
0.71073
monoclinic
P21/n
13.564 (11), 90
6.150 (5), 95.286 (17)
16.469 (13), 90
1368.0 (19)
1850354
C17H13N3·0.5(HO)
Molecular weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
267.81
296
0.71073
Monoclinic,
C2/c
23.909 (3), 90
9.6366 (12), 133.402(6)
17.121 (2), 90
2866.1(6)
o
a (Å), α ( )
o
b (Å), β ( )
o
c (Å), γ ( )
3
Volume (A )
Z
4
8
3
Calculated density (Mg/m )
Absorption coefficient (mm−1
F(000)
1.264
0.079
544
1.241
0.078
1124
)
Crystal size (mm)
Theta range for data collection
0.15 × 0.12 × 0.11
2.51 to 24.98 deg.
–17 ≤ h ≤ 17, –7 ≤ k ≤ 9,
–20 ≤ l ≤ 20
3589/3375 [R(int) = 0.034]
28.32◦ 99.4%
Integration
Full-matrix least-squares on F
3375 / 0 / 181
1.043
0.19 × 0.18 × 0.15
5.84 to 21.45 deg.
–9 ≤ h ≤ 16, –6 ≤ k ≤ 3,
–19 ≤ l ≤ 3
0.13 × 0.12 × 0.11
2.38 to 22.06 deg.
–31 ≤ h ≤ 31, –12 ≤ k ≤ 10,
–22 ≤ l ≤ 22
11593/3595 [R(int) = 0.052]
28.52◦ 98.7%
Integration
Full-matrix least-squares on F
3595 / 0 / 190
1.326
Limiting indices
Reflections collected / unique
Completeness to theta
Absorption correction
Refinement method
Data / restraints / parameters
2031/1782 [R(int) = 0.023]
25.00◦ 73.9%
Integration
2
2
2
Full-matrix least-squares on F
1782 / 0 / 181
1.024
2
Goodness-of-fit on F
Final R indices [I>2sigma(I)]
R indices (all data)
R1 = 0.0448, wR2 = 0.1074
R1 = 0.0722, wR2 = 0.1218
0.12 and –0.20
R1 = 0.0544, wR2 = 0.1233
R1 = 0.0868, wR2 = 0.1500
0.11 and –0.11
R1 = 0.1087, wR2 = 0.3751
R1 = 0.1574, wR2 = 0.4056
0.30 and –0.24
Largest diff. peak and hole(e.A−3
)
Table 4. Selected bond lengths (Å) of the compounds.
Bond distances (Å)
9a
9′a
10a
N(3)-C(10) 1.448(2) N(2)-C(7) 1.448(4)
C(8)-C(10) 1.508(2) C(8)-C(7) 1.512(4)
N(2)-C(10) 1.448(5)
C(8)-C(10) 1.510(5)
N(3)-C(9) 1.131(5)
N(4)-C(9) 1.139(2)
C(7)-C(8) 1.329(2)
N(2)-N(3) 1.345(2)
N(1)-N(2) 1.297(2)
C(8)-C(9) 1.426(2)
N(4)-C(9) 1.139(4)
C(8)-C(10) 1.325(3) C(7)-C(8) 1.323(5)
N(1)-N(2) 1.318(3)
N(2)-N(3) 1.313(3)
C(8)-C(9) 1.408(5)
N(2)-C(11) 1.331(5)
N(1)-C(11) 1.293(6)
C(8)-C(9) 1.416(5)
The proposed mechanism shown in Scheme 5 is a one-pot reaction which is first initiated by acylation of
hydroxyl group in Baylis-Hillman adducts. This is followed by Michael addition of azole anion to alkene which
leads to the elimination of acetyl group to afford the desired N -substituted azole acrylonitriles.
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AYDIN et al./Turk J Chem
Scheme 5. Possible mechanism for N -substituted azole acrylonitriles.
2.1. Conclusion
In conclusion, a very efficient protocol was introduced here as the sole method to access N -substituted-2-
((azolyl) methyl)-3-arylacrylonitriles. Considering readily available reagents, mild reaction conditions and good
stereo- and regioselectivity, this method is valuable for the preparation of compounds coupled with a heterocyclic
skeleton of great biological value.
3. Experimental
3.1. General procedure
All chemicals were purchased from commercial suppliers and used without further purification. Reactions were
monitored by thin layer chromatography (TLC) and visualized under UV light. Melting points were recorded
1
13
on Mettler Toledo MP90 apparatus and are uncorrected. The H (500 MHz) and C (400 MHz) NMR spectra
were recorded on a Bruker Advance 500 DPX spectrometer in CDCl3 . The 2D NOESY spectra were recorded
on an Agilent DD2 400 MHz spectrometer in CDCl3 . The IR spectra were recorded on Perkin Elmer 100
FTIR. The HRMS spectra were recorded on a Shimadzu hybrid LC-MS-IT-TOF spectrometer. Single crystal
data collection was performed on a Bruker AXS APEX CCD diffractometer equipped with a Mo Kα radiation
(λ = 0.71073) source at 296 K. The data process was done with the Bruker SMART program package [33].
Using Olex2 [34], the structures were solved with the SHELXT [35] structure solution program using direct
methods and refined with the same refinement package using the direct methods and refined with full-matrix
2
least squares methods on F .
3.2. Synthesis of N-substituted-2-((1- and 2-benzotriazolyl)methyl)-3-acrylonitriles (9a–i) (9’a,
9’c, 9’i)
To a solution of a convenient Baylis-Hillman nitrile 1 (1 mmol) and N -acetylbenzotriazole (1 mmol, 161 mg) in
DMF (5 mL), K2 CO3 (1 mmol, 138 mg) was added and the resulting mixture was stirred at room temperature
until the starting materials disappeared on TLC. Then, water (20 mL) was poured into the reaction mixture
and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with brine and
dried over anhydrous Na2 SO4 . After the removal of solvent under reduced pressure, the residue was purified
by flash chromatography over silica gel with Ethyl acetate: Hexane (1:3) and crystallized in diethyl ether.
3.2.1. (Z)-2-((1-benzotriazolyl)methyl)-3-phenylacrylonitrile (9a)
White solid; Yield (197 mg, 76%); mp. 104.2 ◦ C; IR υmax (KBr): 2209 cm−1 (CN), 3050, 3086 cm−1 (aromatic
1
C-H), 1452, 1496, 1615 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.13 (d, J = 8.3 Hz, 1H), 7.77
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(d, J = 6.8 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.44 (m, 4H), 7.23 (s, 1H), 5.59 (s, 2H);
13
C NMR (125 MHz, CDCl3): 147.4, 146.3, 132.8, 132.1, 131.5, 129.3, 129.1, 128.3, 124.5, 120.4, 117.2, 109,3,
+
104.7, 51.4; HRMS (ESI): m/z [M+H] calcd for C16 H12 N4 : 261.1135; found: 261.1137.
3.2.2. (Z)-2-((2-benzotriazolyl)methyl)-3-phenylacrylonitrile (9’a)
White solid; Yield (29 mg, 11%); mp. 101.4 ◦ C; IR υmax (KBr): 2215 cm−1 (CN), 3019, 3062, 3091 cm−1
1
(aromatic C-H), 1449, 1495, 1620 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 7.92 (m, 2H), 7.83
13
(d, J = 6.8 Hz, 2H), 7.45 (m, 5H), 7.35 (s, 1H), 5.64 (s, 2H); C NMR (125 MHz, CDCl3): 148.3, 144.9,
+
132.3, 131.5, 129.4, 129.0, 127.0, 118.3, 116.9, 104.6, 59.6; HRMS (ESI): m/z [M+H] calcd for C16 H12 N4 :
261.1124; found: 261.1137.
3.2.3. (Z)-2-((1-benzotriazolyl)methyl)-3-(p-tolyl)acrylonitrile (9b)
Yellow solid; Yield (194 mg, 71%); mp. 120.9 ◦ C; IR υmax (KBr): 2236 cm−1 (CN), 3033, 3065, 3089 cm−1
1
(aromatic C-H), 1455, 1493, 1608 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.13 (d, J = 8.2 Hz,
1H), 7.68 (m, 3H), 7.57 (t, J = 7.9 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.20 (s, 1H),
13
5.57 (s, 2H) 2.40 (s, 3H); C NMR (125 MHz, CDCl3): 147.5, 146.3, 142.3, 132.8, 129.8, 129.5, 129.3, 128.2,
+
124.4, 120.4, 117.5, 109.3, 103.3, 51.2, 21.6; HRMS (ESI): m/z [M+H] calcd for C17 H14 N4 : 275.1291; found:
275.1296.
3.2.4. (Z)-2-((1-benzotriazolyl)methyl)-3-(4-methoxyphenyl)acrylonitrile (9c)
White solid; Yield (195 mg, 67%); mp. 105.1 ◦ C; IR υmax (KBr): 2204 cm−1 (CN), 3049, 3066, 3078 cm−1
1
(aromatic C-H), 1442, 1548, 1600 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.13 (d, J = 8.2 Hz,
1H), 7.77 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.18
13
(s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 5.66 (s, 2H), 3.86 (s, 3H); C NMR (125 MHz, CDCl3): 162.2, 147.1, 131.7,
+
131.3, 128.2, 124.9, 124.4, 120.4, 117.9, 114.8, 114.5, 109.4, 101.2, 55.5, 51.6, 21.6; HRMS (ESI): m/z [M+H]
calcd for C17 H14 N4 O: 291.1240; found: 291.1251.
3.2.5. (Z)-2-((2-benzotriazolyl)methyl)-3-(4-methoxyphenyl)acrylonitrile (9’c)
Yellow solid; Yield (50 mg, 17%); mp. 98.3 ◦ C; IR υmax (KBr): 2254 cm−1 (CN), 3014, 3025, 3043 cm−1
1
(aromatic C-H), 1450, 1514, 1600 cm−1 (aromatic C = C); H NMR (500 MHz, CDCl3): 7.91 (dd, J = 3.1,
6.6 Hz, 2H), 7.83 (d, J = 8.9 Hz, 2H), 7.43 (dd, J = 3.3, 6.7 Hz, 2H), 7.30 (s, 1H), 6.96 (d, J = 8.8 Hz, 2H),
13
5.60 (s, 2H), 3,87(s, 3H); C NMR (125 MHz, CDCl3): 162.1, 148.1, 144.9, 131.5, 126.9, 125.1, 118.3, 117.5,
+
114.4, 101.2, 59.9, 55.5; HRMS (ESI): m/z [M+H] calcd for C17 H14 N4 O: 291.1240; found: 291.1250.
3.2.6. (Z)-2-((1-benzotriazolyl)methyl)-3-(4-fluorophenyl)acrylonitrile (9d)
Yellow solid; Yield (185 mg, 67%); mp. 109.1–114.3 ◦ C; IR υmax (KBr): 2214 cm−1 (CN), 3041, 3065 cm−1
1
(aromatic C-H), 1421, 1509, 1600 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.14 (d, J = 8.2 Hz,
1H), 7.78 (dd, J = 5.3, 8.7 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.3 Hz,
13
1H), 7.18 (s, 1H), 7.13 (t, J = 8.7 Hz, 2H), 5.58 (s, 2H); C NMR (125 MHz, CDCl3): 165.3, 146.3, 146.0,
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AYDIN et al./Turk J Chem
+
132.8, 131.5, 128.5, 128.3, 124.5, 120.4, 117.1, 116.4, 109.2, 104.4, 51.3; HRMS (ESI): m/z [M+H] calcd for
C16 H11 N4 F: 279.1046; found: 279.1041.
3.2.7. (Z)-2-((1-benzotriazolyl)methyl)-3-(3-chlorophenyl)acrylonitrile (9e)
White solid; Yield (186 mg, 63%); mp. 130.5–131.9 ◦ C; IR υmax (KBr): 2263 cm−1 (CN), 3027, 3063 cm−1
1
(aromatic C-H), 1452, 1568, 1614 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.15 (d, J = 8.5 Hz,
1H), 7.67 (m, 3H), 7.60 (t, J = 7.6 Hz, 1H), 7.46 (m, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.11 (s, 1H), 5.59 (s, 2H);
13
C NMR (125 MHz, CDCl3): 146.3, 145.5, 135.1, 133.8, 132.8, 131.4, 130.3, 129.3, 128.4, 127.0, 124.6, 120.6,
+
116.6, 109.1, 106.9, 51.1; HRMS (ESI): m/z [M+H] calcd for C16 H11 N4 Cl: 295.0750; found: 295.0745.
3.2.8. (Z)-2-((1-benzotriazolyl)methyl)-3-(2,4-dichlorophenyl)acrylonitrile (9f)
Orange solid; Yield (171 mg, 52%); mp. 130.8–136.3 ◦ C; IR υmax (KBr): 2222 cm−1 (CN), 3034, 3075 cm−1
1
(aromatic C-H), 1453, 1470, 1586 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.15 (d, J = 8.5 Hz,
1H), 7.92 (d, J = 8,5 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.46 (m, 3H), 7.35 (d, J = 6.9 Hz,
13
1H), 5.63 (s, 2H); C NMR (125 MHz, CDCl3): 146.3, 142.5, 137.7, 135.3, 132.8, 130.0, 129.9, 129.1, 128.4,
+
127.9, 124.6, 120.6, 116.1, 109.1, 108.8, 51.0; HRMS (ESI): m/z [M+H] calcd for C16 H11 N4 Cl2 : 329.0355;
found: 329.0356.
3.2.9. (Z)-2-((1-benzotriazolyl)methyl)-3-(4-bromophenyl)acrylonitrile (9g)
White solid; Yield (214 mg, 63%); mp. 107.7–110.3 ◦ C; IR υmax (KBr): 2232 cm−1 (CN), 3032, 3040, 3068
1
cm−1 (aromatic C-H), 1458, 1507, 1610 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.14 (d, J = 8.5
13
Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.58 (m, 5H), 7.46 (t, J = 7,8 Hz, 1H), 7.14 (s, 1H), 5.58 (s, 2H); C NMR
(125 MHz, CDCl3): 146.2, 146.0, 132.8, 132.4, 130.9, 130.6, 128.4, 126.1, 124.6, 120.5, 117.0, 109.2, 105.5, 51.2;
+
HRMS (ESI): m/z [M+H] calcd for C16 H11 N4 Br: 339.0255; found: 339.0240.
3.2.10. (Z)-2-((1-benzotriazolyl)methyl)-3-(2-furanyl)acrylonitrile (9h)
Green solid; Yield (143 mg, 57%); mp. 114.6 ◦ C; IR υmax (KBr): 2215 cm−1 (CN), 3043 cm−1 (aromatic
1
C-H), 1445, 1546, 1610 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.13 (d, J = 7.5 Hz, 1H), 7.66
(d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 3.5 Hz, 1H), 6.97 (s, 1H)
13
6.54 (m, 1H), 5.54 (s, 2H); C NMR (125 MHz, CDCl3): 148.5, 146.3, 145.8, 133.4, 132.7, 128.3, 124.5, 120.4,
+
117.2, 116.3, 112.8, 109,3, 100.5, 50.5; HRMS (ESI): m/z [M+H] calcd for C14 H10 N4 O: 251.0934; found:
251.0927.
3.2.11. (Z)-2-((1-benzotriazolyl)methyl)-3-(2-thiophenyl)acrylonitrile (9i)
White solid; Yield (75 mg, 28%); mp. 135.0–138.5 ◦ C; IR υmax (KBr): 2242 cm−1 (CN), 3035, 3078, 3091
1
cm−1 (aromatic C-H), 1453, 1493, 1613 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.13 (d, J = 8.2
Hz, 1H), 7.67 (d, J = 8,2 Hz, 1H), 7.57 (m, 3H), 7.45 (t, J = 7,8 Hz, 1H), 7.36 (s, 1H), 7.13 (t, J = 4.9 Hz, 1H),
13
5.56 (s, 2H); C NMR (125 MHz, CDCl3): 146.3, 139.9, 136.1, 133.5, 132.8, 131.3, 128.3, 127.9, 124.5, 120.4,
+
117.5, 109.3, 101.0, 50.7; HRMS (ESI): m/z [M+H] calcd for C14 H10 N4 S: 267.0699; found: 267.0705.
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AYDIN et al./Turk J Chem
3.2.12. (Z)-2-((2-benzotriazolyl)methyl)-3-(2-thiophenyl)acrylonitrile (9’i)
Yellow solid; Yield (30 mg, 11%); mp. 131.4–133.2 ◦ C; IR υmax (KBr): 2205 cm−1 (CN), 3043 cm−1 (aromatic
1
C-H), 1448, 1458, 1614 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 7.91 (dd, J = 3.2, 6.6 Hz, 2H),
13
7.60 (m, 2H), 7.49 (s, 1H), 7.43 (dd, J = 3.2, 6.7 Hz, 2H), 7.14 (t, J = 8.9 Hz, 1H), 5.61 (s, 2H); C NMR
(125 MHz, CDCl3): 144.9, 140.8, 136.3, 133.5, 131.3, 127.8, 127.0, 118.3, 117.1, 101.3, 59.1; HRMS (ESI): m/z
+
[M+H] calcd for C14 H10 N4 S: 267.0699; found: 267.0703.
3.3. Synthesis of N-substituted-2-((benzimidazolyl)methyl)-3-acrylonitriles (10a-i)
To a solution of a convenient Baylis-Hillman acetate 1 (1 mmol) and N -acetylbenzimidazole (1 mmol, 160
mg) in DMF (5 mL), K2 CO3 (1 mmol, 138 mg) was added and the resulting mixture was stirred at room
temperature until the starting materials disappeared on TLC. Then, water (20 mL) was poured into the
reaction mixture and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed
with brine and dried over anhydrous Na2 SO4 . After the removal of solvent under reduced pressure, the residue
was purified by flash chromatography over silica gel with Ethyl acetate: Hexane (1:3) and then crystallized in
diethyl ether.
3.3.1. (Z)-2-((1-benzoimidazolyl)methyl)-3-phenylacrylonitrile (10a)
White solid; Yield (189 mg, 73%); mp. 92.2 ◦ C; IR υmax (KBr): 2213 cm−1 (CN), 3026, 3044, 3068 cm−1
1
(aromatic C-H), 1458, 1500, 1614 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.03 (s, 1H), 7.88 (m,
13
1H), 7.72 (s, 2H), 7.43 (m, 4H), 7.34 (s, 2H), 7.01 (s, 1H), 5.08 (s, 2H); C NMR (125 MHz, CDCl3): 145.6,
144.0, 142.9, 133.4, 132.1, 131.4, 129.1, 129.0, 123.7, 122.9, 120.9, 117.0, 109.6, 105.7, 48.5; HRMS (ESI): m/z
+
[M+H] calcd for C17 H13 N3 : 260.1182; found: 260.1184.
3.3.2. (Z)-2-((1-benzoimidazolyl)methyl)-3-(p-tolyl)acrylonitrile (10b)
White solid; Yield (154 mg, 56%); mp. 85.8 ◦ C; IR υmax (KBr): 2267 cm−1 (CN), 3035, 3076 cm−1 (aromatic
1
C-H), 1460, 1489, 1613 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.13 (d, J = 8.5 Hz, 1H), 7.69
13
(d, J = 8.5 Hz, 2H), 7.56 (m, 5H), 7.45 (m, 2H), 5.58 (s, 2H), 1.28 (s, 3H); C NMR (125 MHz, CDCl3):
147.8, 146.1, 133.0, 132.6, 132.1, 131.1, 130.9, 128.3, 125.4, 124.5, 120.5, 118.1, 109.8, 109.1, 46.0, 29.7; HRMS
+
(ESI): m/z [M+H] calcd for C18 H15 N3 : 274.1339; found: 274.1348.
3.3.3. (Z)-2-((1-benzoimidazolyl)methyl)-3-(4-methoxyphenyl)acrylonitrile (10c)
White solid; Yield (139 mg, 48%); mp. 109.3 ◦ C; IR υmax (KBr): 2234 cm−1 (CN), 3035, 3058, 3087 cm−1
1
(aromatic C-H), 1494, 1513, 1601cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.04 (s, 1H), 7.87 (m,
1H), 7.73 (d, J = 8.8 Hz, 2H), 7.44 (m, 1H), 7.36 (m, 2H), 6.95 (t, J = 8.8 Hz, 3H), 5.07 (s, 2H), 3.86 (s, 3H);
13
C NMR (125 MHz, CDCl3): 162.0, 145.3, 144.0, 142.9, 133.4, 131.4, 131.2, 124.9, 123.7, 122.8, 120.9, 114.5,
+
109.7, 102.3, 55.5, 48.7; HRMS (ESI): m/z [M+H] calcd for C18 H15 N3 O: 290.1288; found: 290.1295.
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AYDIN et al./Turk J Chem
3.3.4. (Z)-2-((1-benzoimidazolyl)methyl)-3-(4-fluorophenyl)acrylonitrile (10d)
White solid; Yield (132 mg, 48%); mp. 110.8 ◦ C; IR υmax (KBr): 2212 cm−1 (CN), 3037, 3079 cm−1 (aromatic
1
C-H), 1464, 1511, 1599 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.04 (s, 1H), 7.88 (dd, J = 3.1,
6.0 Hz, 1H), 7.44 (dd, J = 3.2, 8.5 Hz, 2H), 7.42 (m, 1H), 7.36 (m, 2H), 7.13 (t, J = 8.7 Hz, 2H), 6.95 (s, 1H),
13
5.10 (s, 2H); C NMR (125 MHz, CDCl3): 165.2, 146.8, 144.1, 142.9, 133.4, 131.4, 128.4, 123.8, 122.9, 121.0,
+
116.9, 116.4, 109.5, 105.3, 48.4; HRMS (ESI): m/z [M+H] calcd for C17 H12 N3 F: 278.1088; found: 278.1094.
3.3.5. (Z)-2-((1-benzoimidazolyl)methyl)-3-(3-chlorophenyl)acrylonitrile (10e)
Yellow solid; Yield (141 mg, 48%); mp. 126.5 ◦ C; IR υmax (KBr): 2260 cm−1 (CN), 3029, 3078 cm−1 (aromatic
1
C-H), 1460, 1497, 1616 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.04 (s, 1H), 7.89 (m, 1H), 7.64
13
(t, J = 8.4 Hz, 2H), 7.38 (m, 5H), 6.90 (s, 1H), 5.11 (s, 2H); C NMR (125 MHz, CDCl3): 144.0, 143.6, 142.9,
135.1, 133.7, 133.3, 131.3, 130.4, 129.2, 126.9, 123.9, 123.0, 121.0, 116.4, 109.5, 107.6, 48.3; HRMS (ESI): m/z
+
[M+H] calcd for C17 H12 N3 Cl: 294.0793; found: 294.0806.
3.3.6. (Z)-2-((1-benzoimidazolyl)methyl)-3-(2,4-dichlorophenyl)acrylonitrile (10f)
Light brown solid; Yield (128 mg, 39%); mp. 144.7 ◦ C; IR υmax (KBr): 2218 cm−1 (CN), 3078, 3098 cm−1
1
(aromatic C-H), 1457, 1496, 1584 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.05 (s, 1H), 7.89 (d,
13
J = 6.1 Hz, 2H), 7.47 (s, 1H), 7.44 (d, J = 9.2 Hz, 1H), 7.35 (m, 4H), 5.15 (s, 2H); C NMR (125 MHz,
CDCl3): 144.0, 142.8, 141.2, 137.6, 135.2, 133.2, 130.0, 129.8, 129.1, 127.8, 123.9, 123.0, 121.0, 115.9, 109.8,
+
109.5, 48.3; HRMS (ESI): m/z [M+H] calcd for C17 H12 N3 Cl2 : 328.0403; found: 328.0407.
3.3.7. (Z)-2-((1-benzoimidazolyl)methyl)-3-(4-bromophenyl)acrylonitrile (10g)
Yellow solid; Yield (149 mg, 44%); mp. 129.2 ◦ C; IR υmax (KBr): 2215 cm−1 (CN), 3043, 3076 cm−1 (aromatic
1
C-H), 1460, 1510, 1613 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.02 (s, 1H), 7.87 (t, J = 4.6 Hz,
13
1H), 7.56 (m, 4H), 7.40 (m, 1H), 7.35 (m, 2H), 6.91 (s, 1H), 5.07 (s, 2H); C NMR (125 MHz, CDCl3): 144.1,
143.9, 142.9, 133.3, 132.4, 130.9, 130.5, 125.9, 123.9, 123.0, 120.9, 116.7, 109.5, 106.6, 48.4; HRMS (ESI): m/z
+
[M+H] calcd for C17 H12 N3 Br: 338.0287; found: 338.0283.
3.3.8. (Z)-2-((1-benzoimidazolyl)methyl)-3-(2-furanyl)acrylonitrile (10h)
Yellow solid; Yield (100 mg, 40%); mp. 98.1 ◦ C; IR υmax (KBr): 2214 cm−1 (CN), 3043, 3067, 3097 cm−1
1
(aromatic C-H), 1460, 1497, 1614 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.02 (s, 1H), 7.88 (m,
1H), 7.58 (s, 1H), 7.37 (m, 3H), 6.97 (d, J = 3.8 Hz, 1H), 6.75 (s, 1H), 6.54 (t, J = 1.6 Hz, 1H), 5.06 (s, 2H);
13
C NMR (125 MHz, CDCl3): 148.4, 145.6, 144.0, 142.8, 133.3, 131.6, 123.8, 122.9, 120.9, 116.9, 116.5, 112.7,
+
109.6, 101.7, 47.6; HRMS (ESI): m/z [M+H] calcd for C15 H11 N3 O: 250.0975; found: 250.0982.
3.3.9. (Z)-2-((1-benzoimidazolyl)methyl)-3-(2-thiophenyl)acrylonitrile (10i)
White solid; Yield (127 mg, 48%); mp. 128.4 ◦ C; IR υmax (KBr): 2231 cm−1 (CN), 3026, 3058, 3080 cm−1
1
(aromatic C-H), 1462, 1496, 1618 cm−1 (aromatic C=C); H NMR (500 MHz, CDCl3): 8.03 (s, 1H), 7.88 (m,
1H), 7.57 (d, J = 5.0 Hz, 1H), 7.51 (d, J = 3.4 Hz, 1H), 7.44 (m, 1H), 7.36 (m, 2H), 7.12 (m, 2H), 5.08 (s, 2H);
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AYDIN et al./Turk J Chem
13
C NMR (125 MHz, CDCl3): 144.0, 142.8, 137.9, 136.1, 133.4, 133.2, 131.0, 127.9, 123.8, 122.9, 120.9, 117.2,
+
109.6, 102.2, 47.8; HRMS (ESI): m/z [M+H] calcd for C15 H11 N3 S: 266.0746; found: 266.0750.
Acknowledgment
This work was supported financially by Anadolu University (Project No: 1110F162).
References
1. Al-Omran F, Mohareb RM, El-Khair AA. Synthesis and biological effects of new derivatives of benzotriazole as an-
timicrobial and antifungal agents. Journal of Heterocyclic Chemistry 2002; 39: 877-883. doi: 10.1002/jhet.5570390504
2. Moon WS, Chung KH, Seol DJ, Park ES, Shim JH et al. Antimicrobial effect of monomers and polymers with
azole moieties. Journal of Applied Polymer Science 2003; 90: 2933-2937. doi: 10.1002/app.13019
3. Al-Soud YA, Al-Masoudib NA, Ferwanah AES. Synthesis and properties of new substituted 1,2,4-triazoles: Poten-
tial antitumor agents. Bioorganic and Medicinal Chemistry 2003; 11: 1701-1708. doi: 10.1016/S0968-0896(03)00043-
9
4. Pawar SS, Gorde PL, Kakde RB. Synthesis of new N1 -substituted benzotriazoles as anthelmintic agents. Archives
of Applied Science Research 2010; 2 (1): 80-85.
5. Kopanska K, Najda A, Zebrowska J, Chomicz L, Piekarczyk J et al. Synthesis and activity of 1H -benzimidazole
and 1H -benzotriazole derivatives as inhibitors of Acanthamoeba castellanii. Bioorganic and Medicinal Chemistry
2004; 12: 2617-2624. doi: 10.1016/j.bmc.2004.03.022
6. Suma BV, Natesh NN, Madhavan V. Benzotriazole in medicinal chemistry: An overview. Journal of Chemical and
Pharmaceutical Research 2011; 3 (6): 375-381.
7. Walia R, Hedaitullah M, Naaz S F, Iqbal K, Lamba H. Benzimidazole derivatives – an overview. International
Journal of Research in Pharmacy and Chemistry. 2011; 1 (3): 565-574.
8. Velik J, Baliharova V, Fink-Gremmels J, Bull S, Lamka J et al. Benzimidazole drugs and modulation of biotrans-
formation enzymes. Research in Veterinary Science 2004; 76: 95-108. doi: 10.1016/j.rvsc.2003.08.005
9. Carlini P, Bria E, Giannarelli D, Ferretti G, Felici A et al. New aromatase inhibitors as second-line endocrine
therapy in postmenopausal patients with metastatic breast carcinoma. Cancer 2005; 104 (7): 1335-1342. doi:
10.1002/cncr.21339
10. Joss RA, Galeazzi RL, Bischoff AK, Brunner KW. Alizapride, a new substituted benzamide, as an antiemetic during
cancer chemotherapy. European Journal of Clinical Pharmacology 1985; 27: 721-725. doi: 10.1007/BF00547056
11. Asteinza J Camacho-Carranza R, Reyes-Reyes R E, Dorado-González V Espinosa-Aguirre JJ. Induction of cy-
tochrome P450 enzymes by albendazole treatment in the rat. Environmental Toxicology and Pharmacology 2000;
9: 31-37. doi: 10.1016/S1382-6689(00)00059-4
12. Radice S, Marabini L, Gervasoni M, Ferraris M, Chiesara E. Carbendazim and n-butylisocyanate: metabolites
responsible for benomyl double action on cytochrome P450 in HepG2 cells. Toxicology 1997; 123: 135-142. doi:
10.1016/S0300-483X(97)00122-4
13. Saczewski F, Stencel A, Bienczak A M, Langowska K A, Michaelis M et al. Structure-activity relationships of novel
heteroaryl-acrylonitriles as cytotoxic and antibacterial agents. European Journal of Medicinal Chemistry 2008; 43:
1847-1857. doi: 10.1016/j.ejmech.2007.11.017
14. Carta A, Briguglio I, Piras S, Boatto G, La Colla P et al. 3-Aryl-2-[1H-benzotriazol-1-yl]acrylonitriles: A novel class
of potent tubulin inhibitors. European Journal of Medicinal Chemistry 2011; 46: 4151-4167. doi: 10.1016/j.ejmech.
2011.06.018
1146

AYDIN et al./Turk J Chem
15. Sanna P, Carta A, Gherardini L, Nikookar M E R. Synthesis and antimycobacterial activity of 3-aryl-, 3-cyclohexyl-
and 3-heteroaryl-substituted-2-(1H (2H)-benzotriazol-1(2)-yl)prop-2-enenitriles, prop-2-enamides and propenoic
acids. Il Farmaco 2002; 57: 79-87. doi: 10.1016/S0014-827X(01)01174-0
16. Lee H S, Kim S H, Gowrisankar S, Kim J N. Palladium-mediated synthesis of poly-fused heterocycles from Baylis–
Hillman adducts. Tetrahedron 2008; 64: 7183-7190. doi: 10.1016/j.tet.2008.05.087
17. Lima-Junior CG, Vasconcellos MLAA. Morita–Baylis–Hillman adducts: Biological activities and potentialities to
the discovery of new cheaper drugs. Bioorganic & Medicinal Chemistry 2012; 20: 3954-3971. doi: 10.1016/j.bmc.
2012.04.061
18. Özenç AK, Çelik İ, Kökten Ş. Stereoselective and regioselective synthesis of N -substituted methyl 2-((azolyl)methyl)-
3-arylacrylates from Baylis-Hillman acetates. Turkish Journal of Chemistry 2017; 41: 323-334. doi: 10.3906/kim-
1607-35
19. Celik I, Abdel-Fattah AAA. Convenient synthesis of C-terminal di- and tri-peptide amides from N-protected
dipeptidoylbenzotriazoles. Tetrahedron 2009; 65: 4923-4929. doi: 10.1016/j.tet.2009.02.070
20. Kanışkan N, Kökten Ş, Çelik İ. A new protocol for the synthesis of primary, secondary and tertiary anthranilamides
utilizing N -(2-aminoarylacyl)benzotriazoles. Arkivoc 2012; viii: 198-213. doi: 10.3998/ark.5550190.0013.818
21. Kökten Ş, Çelik İ. A simple, mild, and practical method for the esterification and thioesterification of anthranilic
acid utilizing N -(2-aminobenzoyl)benzotriazole. Synthesis 2013; 45: 2551-2556. doi: 10.1055/s-0033-1339469
22. Leiris SJ, Khdour OM, Segerman ZJ, Tsosie KS, Chapuis J-C et al. Synthesis and evaluation of verticipyrone
analogues as mitochondrial complex I inhibitors. Bioorganic and Medicinal Chemistry 2010; 18: 3481-3493. doi:
10.1016/j.bmc.2010.03.070
23. Lim D, Fang F, Zhou G, Coltart M. Direct carbon-carbon bond formation via soft enolization: A facile and efficient
synthesis of 1,3-diketones. Organic Letters 2007; 9 (21): 4139-4142. doi: 10.1021/ol701599v
24. Chaturvedi AK, Rastog N. Formal acylamination of nitroalkenes in aqueous medium for the synthesis of 2-aryl-3-
nitro-2,3-dihydroquinolin-4(1H)-ones. Synthesis 2015; 47: 249-255. doi: 10.1055/s-0034-1379112
25. Kökten Ş, Çelik İ. N -(2-Aminobenzoyl)benzotriazole mediated and t-BuOK promoted synthesis of 2-substituted
quinolone 3-carboxylates. Tetrahedron Letters 2015; 56: 6254-6256. doi: 10.1016/j.tetlet.2015.09.109
26. Çelik İ, Yıldız F. Synthesis of 4-hydroxyquinoline-2,3-dicarboxylates using N -(2-aminobenzoyl)benzotriazoles.
Tetrahedron 2017; 73: 3878-3882. doi: 10.1016/j.tet.2017.05.058
27. De Souza ROMA, Pereira VLP, Esteves PM, Vasconcellos MLAA. The Morita–Baylis–Hillman reaction in aqueous–
organic solvent system. Tetrahedron Letters 2008; 49: 5902-5905. doi:10.1016/j.tetlet.2008.07.140
28. Junior CGL, De Assis PAC, Silva FPL, Sousa SCO, De Andrade NG et al. Efficient synthesis of 16 aromatic Morita–
Baylis–Hillman adducts: Biological evaluation on Leishmania amazonensis and Leishmania chagasi. Bioorganic
Chemistry 2010; 38: 279-284. doi:10.1016/j.bioorg.2010.08.002
29. Rodrigues MT, Santos MS, Santos H, Coelho F. 1,1’-Carbonyldiimidazole mediates the synthesis of N -substituted
imidazole derivatives from Morita–Baylis–Hillman adducts. Tetrahedron Letters 2014; 55: 180-183. doi: 10.1016/
j.tetlet.2013.10.146
30. Sanna P, Carta A, Nikookar MER. Synthesis and antitubercular activity of 3-aryl substituted-2-(1H(2H) benzotriazol-
1(2)-yl)acrylonitriles. European Journal of Medicinal Chemistry 2000; 35: 535-543. doi: 10.1016/S0223-5234(00)00144-
6
31. Das J, Rao CVL, Sastry TVRS, Roshaiah M, Sankar P G, et al. Effects of positional and geometrical isomerism
on the biological activity of some novel oxazolidinones. Bioorganic and Medicinal Chemistry Letters 2005; 15:
337-343. doi: 10.1016/j.bmcl.2004.10.073
1147

AYDIN et al./Turk J Chem
32. Li J, Liu YK, Zhang YM. Facile and stereoselective synthesis of N-substituted benzotriazole with Baylis-Hillman
adducts. Chinese Chemical Letters 2006; 37: 877-879.
33. SMART, Madison, WI, USA: Bruker AXS, 2000.
34. Dolomanov OV, Bourhis LJ, Gildea RJ, Howard JAK, Puschmann H. OLEX2: a complete structure solution, refine-
ment and analysis program. Journal of Applied Crystallography 2009; 42: 339-341. doi: 10.1107/S0021889808042726
35. Sheldrick G M. SHELXT – Integrated space-group and crystal-structure determination. Acta Crystallography
Section A 2015; 71: 3-8. doi: 10.1107/S2053273314026370
1148